Recent studies, however, suggest that in mammals lactate also serves as a major circulating carbohydrate fuel. By providing with both a convenient source and sink for carbon 3 (3C) compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis in mammalian cells. The reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen’s ugly duckling is actually a beautiful swan-may reshape the field of energy metabolism.

However, the coin is now turned over again. In a study published in Nature Metabolism on October 30, 2023, researchers from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, and East China University of Science and Technology performed a new study with human senescent cells, and disclosed that these cells are more prone to undergo aerobic glycolysis and produce a large amount of lactate. As senescent cells also sustain mitochondrial respiration, such a special form of metabolic reprogramming sharply differs from “Warburg effect”, a well-known metabolic pattern mostly observed in cancer cells.

“Metabolism plays an important role in regulating cellular senescence, the original driving force of natural aging process”, Dr. SUN Yu, the leader of this study said.

By metabolic profiling and functional assessments of glucose consumption, the group decoded the metabolic password of human senescent cells, and discovered that PDK4, a glycolysis-promoting enzyme, indeed acts as a key regulator of biochemical activities to shape a unique form of metabolism, namely hypercatabolism, in these “aged” cells.

Of note, the group found that lactate promotes ROS production via NOX1 to drive the senescence-associated secretory phenotype (SASP), whereas PDK4 inhibition alleviates DNA damage and limits the SASP development. In preclinical trials, pharmacological suppression of PDK4 prevents physical dysfunction and ameliorates age-associated frailty.

Chronological age-associated cellular senescence in microenvironments bridges the gap between lactate overproduction, chronic inflammation and pathological events, while accumulation of lactate in solid organs is a pivotal and early event in various human disorders.

“Given that PDK4 expression rewires energy metabolism, holds the potential for causing tissue homeostasis imbalance and overall physical dysfunction, the data raise the possibility that PDK4 is specifically targeted to delay natural aging and intervene multiple age-related pathologies, including but not limited to various malignancies”, Dr. SUN Yu shared.

PDK4 mediates hypercatabolism and lactate production of senescent cells, together promoting chronological aging and age-related diseases. (Image provided by Dr. SUN Yu’s group)